Dovonou et al.

Translational
Translational Neurodegeneration (2023) 12:36
https://doi.org/10.1186/s40035-023-00368-8 Neurodegeneration

REVIEW Open Access

Animal models of Parkinson’s disease:

bridging the gap between disease hallmarks
and research questions
Axelle Dovonou1†, Cyril Bolduc1†, Victoria Soto Linan1†, Charles Gora1, Modesto R. Peralta III1 and
Martin Lévesque1,2*   

Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symp-
toms. More than 200 years after its first clinical description, PD remains a serious affliction that affects a growing
proportion of the population. Prevailing treatments only alleviate symptoms; there is still neither a cure that targets
the neurodegenerative processes nor therapies that modify the course of the disease. Over the past decades, several
animal models have been developed to study PD. Although no model precisely recapitulates the pathology, they still
provide valuable information that contributes to our understanding of the disease and the limitations of our treat-
ment options. This review comprehensively summarizes the different animal models available for Parkinson’s research,
with a focus on those induced by drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, and viral
vector injections. We highlight their characteristics and ability to reproduce PD-like phenotypes. It is essential to real-
ize that the strengths and weaknesses of each model and the induction technique at our disposal are determined
by the research question being asked. Our review, therefore, seeks to better aid researchers by ensuring a concrete
discernment of classical and novel animal models in PD research.
Keywords Parkinson’s disease, Animal model, Alpha-synuclein, Transgenic model, Preformed fibril, Mouse

Introduction as resting tremors, rigidity, and bradykinesia [3, 4].

Parkinson’s disease (PD) is the second most common These cardinal symptoms are caused by the degenera-
age-related neurodegenerative disease, affecting up to tion of dopamine (DA) neurons in the substantia nigra
3% of individuals aged 65 and older [1, 2]. The disease pars compacta (SNpc). PD is also accompanied by
is a progressive, multifactorial, and heterogeneous non-motor symptoms, including sleep disorders and
disorder. PD patients show motor dysfunction, such dysfunction, autonomic dysfunction, cognitive and
neuropsychiatric symptoms, gastrointestinal symp-
toms, weight and visual disturbances, and fatigue [2].
†
Axelle Dovonou, Cyril Bolduc and Victoria Soto Linan have contributed The pathology arises alongside the accumulation of
equally to this work Lewy bodies composed of aggregated α-synuclein
*Correspondence: (α-syn). The cause of DA neuronal loss remains
Martin Lévesque unclear, but several pieces of evidence link these
[email protected]
1
CERVO Brain Research Centre, 2601, Chemin de la Canardière, Québec,
neuropathologic processes to impaired proteasomal
QC G1J 2G3, Canada protein clearance, mitochondrial dysfunction, and
2
Department of Psychiatry and Neurosciences, Faculty of Medicine, neuroinflammation [5, 6] (Fig. 1). Despite being well-
Université Laval, Québec, QC, Canada
characterized, the diagnosis of PD is only confirmed

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Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 2 of 25

Fig. 1 The hallmarks of Parkinson’s disease (PD). Predominant PD motor symptoms arise from DA neuron loss in the SNpc, and the denervation
of their axons in the caudate nucleus and putamen, also called the striatum. The cause of PD remains unclear but involves loss of DA neurons, α-syn
aggregation, mitochondrial dysfunction, autophagy impairments, and neuroinflammation. PD patients additionally exhibit non-motor symptoms.
The figure was generated using BioRender.

with a post-mortem autopsy, and what triggers this Drug‑induced parkinsonism

disease is still not clearly understood. Drug-induced parkinsonism (DIP) is the most com-
Animal models have only been able to reproduce mon form of secondary parkinsonism, meaning that
partial signs of the PD pathology. Compared to the in patients, DIP produces symptoms similar to those of
clinical characteristics seen in patients, the onset, pro- PD. Typical symptoms in DIP include olfactory dysfunc-
gression, and disease outcome in these models remain tion, difficulty starting and controlling movement, loss
incomplete. Nevertheless, these animal models are or weakness of movement, and resting tremors [7]. DIP
still necessary to study the complexity of the brain is the second most common cause of parkinsonism after
networks involved in brain pathologies or to evalu- idiopathic PD [8, 9]. In the following subsections, we will
ate the impact of potential therapeutic approaches. summarize existing drug-induced models, which repro-
The choice of the animal model is crucial, and stud- duce several motor impairments in animals but fail to
ies must be interpreted with the inherent limitations of replicate the majority of neuropathologies associated
the paradigm chosen. In this review, we encompass a with PD.
wide range of animal species, including rodents, non-
human primates, and non-mammalian organisms such Reserpine
as Drosophila and C. elegans. Our aim is to provide One of the first animal models of PD was generated with
an updated and comprehensive overview of both con- the injection of reserpine in 1957 by Carlsson and col-
ventional and unconventional animal models of PD, leagues [10]. This molecule is an inhibitor of the vesicu-
including models that have received comparatively less lar monoamine transporter (VMAT) type 2 (Fig. 2) [11].
attention. Moreover, our review goes beyond the pri- Reserpine administration causes monoamine depletion in
mary pathogenic hallmarks of PD and sheds light on nerve terminals by reducing vesicular storage and release.
the secondary traits observed in each model, such as This loss of monoamines leads to hypolocomotion and
mitochondrial and autophagic dysfunctions, as well as muscular rigidity. Firstly used as an antihypertensive drug
neuroinflammation. By offering researchers a valuable due to its capacity to deplete cellular monoamine con-
resource, our review aims to assist them in selecting tent [12], the clinical application of reserpine resulted in
the most relevant animal model that aligns with their patients developing lethargy, depression, and motor dys-
specific scientific questions. kinesia [12–14]. In rodents, administration of reserpine
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 3 of 25

Fig. 2 Schematic summary of the current known mechanisms that trigger DA neuron death, and the action of different genes and compounds
used to model PD. The loss of DA neurons could result from impaired protein degradation, mitochondrial dysfunction, α-syn aggregation,
and neuroinflammation, which can be induced by neurotoxic or genetic alteration. The reduced DA signaling through drug inhibition could
also lead to a PD-like phenotype. LPS: lipopolysaccharide, DAT: dopamine transporter, VMAT: vesicular monoamine transporter, NM: neuromelanin,
DA: dopamine. The figure was generated using BioRender.

induces motor impairment as well as memory, cognitive, reserpine model is not commonly used to study late-
and emotional deficits [15, 16]. Injection of reserpine par- stage hallmarks of PD pathology, because it fails to gener-
tially mimics the pathogenesis of PD, developing akinesia ate Lewy body-like inclusions [19] and permanent loss of
and rigidity that reflect the clinical features of the dis- DA neurons. While there are reports of oxidative stress
ease. Furthermore, the work of Carlsson and colleagues in the striatum of rodents upon treatment with reserpine,
showed that Levodopa (L-DOPA) can partially rescue there is neither indication of mitochondrial or lysosomal
the effect of reserpine administration [10]. In rats, reser- dysfunction, nor inflammation [20]. However, other than
pine administration produces sexually dimorphic impair- memory deficits, reserpine also generates several non-
ments in motor performance, as present in PD [17]. motor features relevant to the preclinical manifestations
Within weeks, DA neuronal loss in the SNpc and fibers of PD, i.e., sleep abnormalities, anxiety, depressive-like
in the dorsal striatum can be seen. However, this pheno- behavior, and gastrointestinal dysfunction [21]. For this
type is transient. A partial recovery of nigral DA neurons reason, reserpine can be used as a model to study the dis-
occurs 30 days post-injection, rescuing motor deficits ease progression and neurochemical features of PD.
[16–18]. It should be noted that no significant loss of DA
axonal innervation in the dorsal striatum is observed in Haloperidol
female rats, which could explain the dimorphic impair- Haloperidol is a typical antipsychotic that binds post-
ments in motor behavior [17]. Overall, reserpine can synaptic dopaminergic D2 receptors [22] (Fig. 2). The
induce PD symptoms in humans and parkinsonian-like block of striatal DA transmission results in abnormal
signs in rodents (Table 1). The facility for adjusting dose downstream firing within the basal ganglia circuits,
concentration and administration allows multiple lev- manifesting muscle rigidity and catalepsy [23, 24].
els of studies of PD symptomatology. Nevertheless, the Acute administration of haloperidol also reduces the
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 4 of 25

striatal content of DA, noradrenaline, and serotonin of rodents with haloperidol results in significant
[25]. A prolonged administration in mice causes mito- increases in the levels of pro-inflammatory cytokines
chondrial complex I (MCI) deficiency in the frontal TNF-α and IL-1β in the cortex and striatum compared
cortex, hippocampus, striatum, and midbrain [26]. The to control animals [35]. However, no midbrain DA
haloperidol model is used for modelling rigidity, dys- neuron degeneration has been reported with haloperi-
kinesia or catalepsy, and for discovering novel antipar- dol. Thus, haloperidol may be less relevant for study-
kinsonian agents in rodents [27–30] and non-human ing novel neuroprotective or neurorepair strategies for
primates [31–34]. Additionally, chronic treatment PD (Table 1).

Table 1 Summary of the pathogenic characteristics observed in PD animal models

Model Species Dopamine Motor deficits α-syn Mitochondrial Autophagic Neuro- Comments
loss pathology dysfunction impairment inflammation

Drug-induced parkinsonism
Reserpine Rodents Yes Yes Yes NR NR NR Oxidative stress
(SNpc and Non-motor phe-
Striatum) notype
Transient loss
of DA neurons
Sexual dimorphic
effect
Haloperidol Rodents, Yes Yes No Yes NR Yes Crosses the BBB
primates (Striatum) Induces features
of neuroinflam-
mation
No loss of SNpc
DA neurons
Neurotoxic animal models
6-OHDA C. elegans*, Yes Yes No Yes Yes Yes Oxidative stress
rodents, (SNpc and Non-motor phe-
primates Striatum) notype
Does not cross the
BBB
MPTP Rodents and Yes Yes Yes Yes Yes Yes Oxidative stress
primates (SNpc and Recreates phases
Striatum) of PD
Non-motor phe-
notype
Phenotype vari-
ability in rodents
LPS Rodents Yes Yes Yes Yes Yes Yes Oxidative stress
(SNpc and Non-motor phe-
Striatum) notype
No α-syn inclu-
sions
Tau pathology
Agrochemical-induced animal models
Rotenone C. elegans*, Yes Yes Yes Yes Yes Yes Oxidative stress
Drosophila* (SNpc and Non-motor phe-
and rodents Striatum) notype
Inter-individual
variability
Paraquat & Maneb C. elegans*, Yes Yes Yes Yes NR Yes Combination
Drosophila* (SNpc) increases toxicity
and rodents Oxidative stress
Non-motor phe-
notype
Intact striatal fib-
ers in rats
Induces pulmo-
nary fibrosis
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 5 of 25

Table 1 (continued)
Model Species Dopamine Motor deficits α-syn Mitochondrial Autophagic Neuro- Comments
loss pathology dysfunction impairment inflammation

Transgenic models
PRKN & PINK1 C. elegans* Yes Yes N/A Yes NR NR Lifespan decreases
(KO)
Drosophila* Yes Yes N/A Yes NR NR Degeneration
(KO) of flight muscles
No DA cell loss
in PRKN ortholog-
KO Drosophila
Mice Yes Yes No Yes No Yes Mitochondrial
(KO) (SNpc dysfunction
and stria- Slow degenera-
tum) tion
Primates Yes Yes NR NR NR NR Years to develop
(KO) (SNpc) the phenotype
LRRK2 C. elegans* Yes Yes N/A Yes Yes NR Progressive loss
(OE) of DA neurons
Drosophila* Yes Yes N/A Yes Yes NR Synaptic altera-
(OE) tions
Tau pathology
Mice Yes Yes Yes Yes Yes Yes Oxidative stress
(OE) (SNpc Synaptic altera-
and Stria- tions
tum) Tau pathology
DJ-1 Mice Yes Yes No Yes Yes NR May target early
(KO) (SNpc phases of pathol-
and Stria- ogy
tum) Age-dependent
phenotype
UCH-L1 Drosophila* Yes Yes N/A NR NR NR Progressive
(KO) age-dependent
loss of SNpc DA
neurons
Mice Yes Yes No NR NR NR Increased vulner-
(OE) (SNpc ability to α-syn
and Stria- Not well charac-
tum) terized
GBA1 Drosophila* Yes Yes N/A NR NR NR Increases aggre-
(KO/KI) gation in mutant
α-syn model
Mice Yes Yes Yes Yes Yes Yes Cognitive deficits
(KI) No α-syn aggre-
gates in GBA1
L444P heterozy-
gous mice
Lmx1a/b Mice Yes Yes Yes Yes Yes NR Altered develop-
(KO) (SNpc ment
and Stria- KO needs to be
tum) performed
on mature animals
Otx2 Mice Yes Yes N/A N/A N/A N/A Loss of DA neu-
(KO) (SNpc rons in the VTA
and Stria- Altered develop-
tum) ment
KO needs to be
performed
on mature animals
Foxa1/2 Mice Yes Yes No N/A N/A N/A Altered develop-
(KO) (SNpc ment
and Stria- KO needs to be
tum) performed
on mature animals
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 6 of 25

Table 1 (continued)
Model Species Dopamine Motor deficits α-syn Mitochondrial Autophagic Neuro- Comments
loss pathology dysfunction impairment inflammation

Pitx3 Mice Yes Yes N/A N/A N/A N/A Altered develop-
(KO) (SNpc ment
and Stria- KO needs to be
tum) performed
on mature animals
Nurr1& En1 Mice Yes Yes N/A N/A N/A N/A Total depletion
(KD) (SNpc is not viable
and Stria- (Altered develop-
tum) ment)
KD needs to be
performed
on mature animals
c-Rel Mice Yes Yes N/A N/A N/A N/A Altered develop-
(KO) (SNpc ment
and Stria- KO needs to be
tum) performed
on mature animals
Mitochondrial impairment Mice No No NR Yes NR NR No phenotypic
(POLG) accentuation
in DJ-1/PRKN
deficient mice
Mice Yes Yes NR Yes NR NR Total reduction
(Ndufs2 KO) (Striatum) of MCI activity
Mouse death
at 5–6 months
Mice Yes No Yes Yes NR NR Partial reduction
(Ndufs4 KO) (Striatum) of MCI activity
No loss in SNpc
α-syn models
WT α-syn Mice Yes Yes Yes Yes NR Yes No degenera-
(M61) (Striatum) tion of SNpc DA
neurons
C. elegans* Yes Yes Yes Yes NR NR No endogenous
and α-syn
Drosophila*
C-terminally truncated Mice Yes Yes Yes NR NR NR Null endogenous
α-syn (MI2) (SNpc α-syn background
and Stria- α-syn expression
tum) restricted to
DA neurons
E46K human α-syn Mice NR Yes Yes NR NR Yes No α-syn in SNpc
(M47 line) DA neurons
A30P human α-syn Mice NR Yes Yes Yes Yes NR Around a year
to develop strong
phenotype
No degenera-
tion of SNpc DA
neurons
C. elegans* Yes Yes Yes Yes NR NR Lower α -syn
and accumulation
Drosophila* than α-syn WT
Lower α -syn
accumulation
than α-synA53T
A53T human α-syn Mice NR Yes Yes Yes Yes Yes α-syn inclusions
(M83 line) in non-PD-related
areas
C. elegans* Yes Yes Yes Yes NR NR No endogenous
and α-syn
Drosophila*
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 7 of 25

Table 1 (continued)
Model Species Dopamine Motor deficits α-syn Mitochondrial Autophagic Neuro- Comments
loss pathology dysfunction impairment inflammation

PFFs Mice Yes Yes Yes NR NR Yes Slow phenotype

development
in WT mice (6
months)
Accelerated phe-
notype in A53T
transgenic mice

Primates Yes NR Yes NR NR NR -

Viral-vector-mediated models
α-synuclein viral expres- Rodents and Yes Yes Yes Yes Yes Yes Progressive neu-
sion primates (SNpc and ronal loss
Striatum) Non-motor phe-
notype
Variable pheno-
type depending
on the injection
Non-physiological
α-syn expression
NM-like production Rodents Yes Yes Yes Yes Yes Yes Age-dependent
(SNpc and progression
Striatum)
* C. elegans and Drosophila do not express endogenous α-synuclein
BBB: blood-brain barrier; KO: Knock-Out; KI: Knock-In; N/A: Not applicable; NM: neuromelanin; NR: Not reported in vivo; OE: Overexpression; PFF: preformed fibril;
POLG: polymerase gamma; SNpc: substantia nigra pars compacta

Neurotoxic models (TH)-positive neurons in the SNpc is delayed by several

6‑Hydroxydopamine (6‑OHDA) days post-surgery [45, 46]. By comparison, an injection
Identified more than 60 years ago [36], the neurotoxin of the neurotoxin into the medial forebrain bundle or
6-OHDA is widely used to model PD by lesioning the directly into the SNpc results in more severe and rapid
nigrostriatal DA system [37–39]. 6-OHDA is a highly neurodegeneration [47]. These injections result in motor
oxidizable DA analogue that transfers through the dopa- impairments and non-motor phenotypes in rodents that
mine transporter (DAT) and the noradrenaline reuptake include cognitive and gastrointestinal dysfunction [48–
transporter. It exerts cytotoxic effects through different 51]. This toxin not only induces a reduced expression of
pathways: production of free radicals, and direct inhi- the lysosomal-associated membrane protein 1, but also
bition of MCI in the respiratory chain [40, 41] (Fig. 2). impairs the hydrolase activities of lysosomal proteases
These different mechanisms may be linked to the genera- [52]. 6-OHDA is not accompanied by α-syn aggrega-
tion of reactive oxygen species (ROS) and the release of tion or the formation of Lewy body-like inclusions. The
cytochrome c, which leads to the activation of astrocytes 6-OHDA model is also used in Caenorhabditis elegans
and microglia [42, 43]. Because 6-OHDA does not cross (C. elegans) [53], mainly for rapid studies such as drug
the blood-brain barrier (BBB), an intracranial injection is screenings. More used in rodents, specifically in rats,
required to exert its toxic effects [44]. In the past, at least the time course and severity of the 6-OHDA PD pattern
three 6-OHDA lesional models have been used to mimic depends on the amount and the injection location in the
PD: an injection into the medial forebrain bundle, the brain. No model has been developed yet for Drosophila
SNpc, or the terminal regions of the nigrostriatal path- melanogaster (D. melanogaster).
way in the striatum. The intravenous co-administration In summary, 6-OHDA is an affordable drug frequently
of desipramine helps protect the noradrenergic system used to generate rapid and specific neurodegeneration
from damage, and allows the targeting of catecholamin- of the nigrostriatal system (Table 1). This model mimics
ergic neurons, such as the DA neurons of the SNpc [40]. several cellular processes identified in PD and is suitable
The 6-OHDA injection in the striatum leads to more for studying the molecular basis of cytotoxicity, oxida-
progressive degeneration of DA neurons. In rodents, tive stress processes, neuroinflammation, and neuronal
axonal denervation can be seen 3 h after injection in death [43, 54, 55]. Although the 6-OHDA model has
the striatum, while reduction of tyrosine hydroxylase many advantages, its course differs from that observed in
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 8 of 25

idiopathic PD, where neuronal degeneration occurs over Gram-negative bacteria and is well-known for its pro-
the years. Despite its limitations, it remains an excellent inflammatory properties. LPS binds the toll-like recep-
tool for studying anti-PD drugs, L-DOPA-induced dyski- tor 4 mainly expressed in microglia [65]. The use of LPS
nesia, or cell transplantation therapy. was initially intended for systemic inflammation models
and the discovery of novel therapies in the treatment of
1‑Methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP) acute inflammation [66, 67]. However, in 2001, a clinical
First discovered in humans, this neurotoxin soon became case report showed that a 22-year-old laboratory worker
a vital research tool in the early 1980s. Mistaken for syn- developed PD syndrome after accidental exposure to
thetic heroin, MPTP produced clinical and pathological Salmonella minnesota LPS through an open wound.
PD features in young drug addicts [56]. After systemic Positron emission tomography confirmed that the sub-
administration, MPTP rapidly crosses the BBB and is ject also suffered from a dopaminergic neuronal loss in
metabolized to MPDP+ (1-methyl-4-phenyl-2,3-dihy- the SNpc [68]. Furthermore, two studies published ear-
dropyridinium) by astrocytes [57]. The active toxic com- lier showed that injecting LPS into the SNpc of rats leads
pound, 1-methyl-4-phenylpyridinium (MPP+), quickly to neurodegeneration of nigral DA neurons [69, 70]. The
enters DA neurons through DAT, where it binds to the neuronal loss is permanent and selective to DA neurons
VMAT and translocates to synaptosomal vesicles or [71]. Since then, several LPS-induced models of PD have
remains within the mitochondria and cytosol (Fig. 2). been developed, but their phenotypes greatly depend on
MPP + leads to an acute deficit in ATP formation and the administration route [65, 72]. LPS can be delivered
ROS production, via binding to MCI, and ends in neu- systemically or locally to the striatum, pallidum, or SNpc
ronal death [58]. Furthermore, MPTP administration through intracerebral injections or intranasally.
drives microglial activation and cytokine release [59]. In While a few studies have used mice, LPS is more com-
humans and non-human primates, MPTP can replicate monly used in rats [73–75]. Intrastriatal and intranigral
almost all the motor impairments of PD, including trem- injection of LPS in rats results in severe neurodegenera-
ors, rigidity, slowness of movement, postural instability, tion of DA neurons from the SNpc with reduced striatal
and freezing [60]. The loss of SNpc DA neurons can also DA and motor impairments within a month [76–83].
be accompanied by an almost complete depletion in DA Reduced MCI and II can be observed in nigral neurons
and associated metabolites in the putamen [61]. It must [78]. A similar phenotype is seen when injecting LPS
be noted that this model is highly variable depending on into the pallidum of rats, but motor impairments appear
the neurotoxin dosage, and the species and strains used. transient and return to normal after a few weeks [84].
Unlike primates, rodents (and variable strains of mice) It should be noted that using older rats can increase
are less sensitive to MPTP toxicity and require multiple the severity of the phenotype [78, 84]. Furthermore, it
doses over several days to induce neuronal degeneration. has been reported that LPS increases the expression of
Thus, an appropriate administration schedule is needed α-syn in the brain [78, 85], the amount of oligomerized
[62]. While mice treated with MPTP do not develop per- α-syn [86], and the expression of cytokines and activated
sistent and progressive motor dysfunctions [60], they are microglia in both the SNpc and the striatum [78, 82].
arguably a viable choice for studying neuroanatomical Overall, local delivery of LPS to the brain generates fea-
and neurochemical alterations. In the SNpc and ventral tures relevant to PD and can thus be used to clarify the
tegmental area (VTA) of treated mice, MPTP causes the role of neuroinflammation in SNpc DA neuron degenera-
loss of more than half of all DA neurons. Recent stud- tion. However, the pathology is limited to the injection
ies show that the administration of MPTP can increase site.
the total and the phosphorylated α-syn as well as tubu- Systemic injection of LPS in mice through intraperito-
lin-associated unit (Tau) in the hippocampus and SNpc neal injection induces loss of DA neurons, motor deficits,
[63]. Hence, MPTP is widely used as a model to study the and α-syn accumulation [85, 87, 88]. Autophagic impair-
molecular and neuropathological events in PD, especially ment has also been described in nigral neurons with
in non-human primates (Table 1). this route of administration [89]. It has been reported
that there may be a delay in the appearance of the phe-
Lipopolysaccharide (LPS)‑induced neuroinflammation notype depending on the recurrence of the dose injected
In PD patients, a dense population of reactive micro- [72]. After a single intraperitoneal injection of LPS in
glia and astrocytes can be found in the brain, accom- mice, neurodegeneration of DA neurons can take sev-
panied by an increased amount of pro-inflammatory eral months [87, 88]; this delay can be reduced to 1 week
cytokines, suggesting that neuroinflammation could play by performing daily injections of LPS [85]. Recently, the
a key role in the pathogenesis [64]. Neuroinflammation administration of LPS through the nasal route in mice
can be modeled using LPS, an endotoxin produced by has gained popularity. A chronic administration via the
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 9 of 25

nasal cavity leads to an approximate loss of 50% of DA Paraquat and Maneb

neurons from the SNpc and reduces the amount of stri- Paraquat is one of the most widely used herbicides in the
atal DA within a month. This phenotype is accompanied world [113]. The mechanism of paraquat leading to PD
by microglial activation, motor deficits, and a twofold remains unclear because it cannot cross the BBB. DAT
increase of expression of α-syn in the SNpc [80, 90]. does not directly transport paraquat, but paraquat can be
Lastly, bilateral administration can also be performed to converted to PQ2+, which seems to be the active agent
increase the severity of the phenotype [91]. This route penetrating the DA neurons through DAT [114] (Fig. 2).
of administration could be used to better understand In rodents, paraquat administered alone has a mild effect
the involvement of environmental exposure through the on nigral neurons. This herbicide induces partial degen-
nasal cavity in developing PD. Overall, LPS-induced PD eration of DA cell bodies in the SNpc, without clear
models are useful in studying the role of neuroinflamma- denervation of striatal fibers or motor impairments [115–
tion in PD (Table 1). However, the LPS-induced models 118]. It also transiently increases the amount of α-syn
could involve a more extensive phenotype that is less spe- protein leading to inclusions within SNpc DA neurons
cific to PD characteristics. In fact, systemic LPS can be [119, 120]. Additionally, paraquat drives neuroinflamma-
used as a chronic inflammation model of Alzheimer’s dis- tion and microglial activation [121]. However, particular
ease since it can cause memory deficits and an increase in attention must be given to the paraquat dose since it can
Tau phosphorylation [92–95]. result in pulmonary fibrosis, which might interfere with
the motor behavioral assessment [122].
Agrochemical‑induced models In agriculture, paraquat is often used in combination
Pesticide exposure is highly associated with PD develop- with other agrochemicals, such as maneb. The com-
ment and is believed to influence its onset significantly. bined administration of paraquat and maneb in rodents
Epidemiological studies found that working in farming increases the toxicity by inducing microglial activation, a
fields and pesticide exposure are positively associated significant loss of DA neurons from the SNpc and stri-
with an increased risk of developing PD [96–98]. Rote- atal fibers, as well as motor impairments [115, 117, 118,
none, paraquat, and maneb are three pesticides that have 123, 124]. However, in rats, the combined exposure does
been linked with PD onset [99, 100]. not seem to affect striatal DA fibers [115, 123]. Over the
last two decades, interest has grown in using paraquat
Rotenone to mimic PD in animal models such as Drosophila [125]
Rotenone was first introduced as a PD model in 2000 and C. elegans [126] since it efficiently causes the loss of
[101]. After systemic administration, the lipophilic prop- DA neurons, and increases ROS levels, cellular dysfunc-
erty of rotenone allows it to cross the BBB and diffuse tion and motor impairments. In these species, this agro-
across the cellular membranes of neurons, inhibiting chemical can be used to perform neuroprotective studies
MCI and proteasomal activity. It induces oxidative stress by fast screening or to study the gene interaction patho-
and α-syn accumulation [102, 103]. In rodents, selec- genesis (Table 1). Although rats are an exception, para-
tive degeneration of the DA neurons from the SNpc and quat and maneb models successfully reproduce many PD
axonal denervation in the striatum arise within weeks, hallmarks.
accompanied by motor impairments and α-syn inclu-
sions [101, 104, 105]. Consistent with what is observed in PD‑associated gene models
idiopathic PD, rotenone activates microglia and impairs It is estimated that up to 10% of diagnosed cases of PD
autophagy [106–108]. In lower-order species, such as C. have a familial origin [2]. Several genes have been iden-
elegans and Drosophila, rotenone can be used to mimic tified as risk factors for PD, including Parkin RBR E3
PD by inducing motor deficits and a loss of DA neurons ubiquitin-protein ligase (PRKN), PTEN-induced putative
[109]. Due to the genetic simplicity of these species, fast kinase 1 (PINK1), Leucine-rich repeat kinas 2 (LRRK2),
screening approaches can be used when looking for novel Daisuke-Junko-1 (DJ-1), ubiquitin carboxy-terminal
neuroprotective targets (Table 1). While rotenone repro- hydrolase L1 (UCH-L1), and β-glucocerebrosidase
duces several features of PD, the main limitation remains (GBA1) [127]. In animals, the manipulation of most of
in its significant inter-individual variability [110, 111]. these genes can mimic some features of idiopathic PD,
This might explain why no studies are reported using such as Lewy body-like formation, and lysosomal and
rotenone in non-human primates since a greater sample mitochondrial dysfunction. The SNCA gene, encoding
size would be required to account for variability [112]. α-syn protein, is also heavily implicated in genetic and
sporadic forms of PD [128]. Existing SNCA transgenic
models will be discussed in the following section.
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 10 of 25

PRKN and PINK1 primates has been generated. This model requires spe-
Of all the familial forms of PD, PRKN is the most fre- cialized expertise and installations to maintain these ani-
quently mutated gene accounting for about 50% of early- mals, which may exceed the technical capacities of many
onset genetic cases, followed by mutations in PINK1, research teams.
which represent up to 8% of early-onset familial forms
of PD [127]. PRKN and PINK1 are both involved in the LRRK2
mitochondrial stress response and are believed to act Mutations in the LRRK2 gene are dominant and account
along the same pathway. Indeed, mitochondrial stress for around 4% of familial cases of PD [139]. LRRK2 is a
leads to the accumulation of PINK1 within mitochon- protein containing both a kinase and a GTPase domain.
dria and initiates autophagy of damaged mitochondria In addition, this gene interacts with many proteins,
through the recruitment of PRKN [129] (Fig. 2). PRKN regulating various cellular functions (Fig. 2), including
and PINK1 mutations are recessive and generally lead to autophagy, mitochondrial functions, and vesicular traf-
a loss of function. Interestingly, almost all clinical cases of ficking [140]. Most LRRK2 mutations, such as G2019S
PRKN-induced parkinsonism lack Lewy body pathology and R1441C/G, affect one of the enzymatic domains.
[130]. Hyperactivity of LRRK2 kinase has also been observed
In C. elegans and Drosophila, genetic deletion of the in idiopathic cases [141]. While DA neuron loss from
ortholog form of human PRKN and PINK1 results in the SNpc is one characteristic of parkinsonian patients
typical Parkinson-like phenotypes. In C. elegans, these carrying a LRRK2 mutation, approximately 21%–54%
mutations are associated with motor impairment, mito- of these clinical cases do not show apparent Lewy bod-
chondrial dysfunction, and loss of DA neurons [131, ies [149, 150], suggesting that this mutation could induce
132]. In Drosophila, PINK1 ortholog deletions lead to the neurodegeneration through another factor than synucle-
development of similar features, with the addition of the inopathy. Some evidence indicates that the toxic effect
degeneration of muscles [133]. PRKN ortholog-deficient might be mediated through the protein Tau, since about
Drosophila have a comparable phenotype, except for 79% of PD patients carrying a LRRK2 mutation show
the absence of DA neuron loss [134]. These models are some features of Tau pathology [142]. In C. elegans and
particularly suitable for fast screening approaches when Drosophila, overexpression of human wild-type (WT) or
studying PRKN/PINK1 regulatory mechanisms involved G2019S and mutated LRRK2 causes motor dysfunctions
in the pathogenicity. In mice, the genetic deletion of and progressive degeneration of DA neurons [144–148].
both PINK1 and PRKN leads to mitochondrial dysfunc- LRRK2 G2019S overexpression in both species results
tion and neuroinflammation without affecting the basal in mitochondrial and autophagic dysfunction [144, 146,
mitophagy. This model does not appear to exhibit α-syn 147, 149]. In Drosophila, overexpression of the G2019S
aggregates, behavioral abnormalities, reduced striatal mutated form of LRRK2 induces a loss of dendritic arbo-
DA levels, or loss of nigral DA neurons [135, 136]. How- rization by hyperphosphorylation of endogenous Tau.
ever, it is possible that neurodegeneration only occurs in Furthermore, overexpression of the Drosophila ortholog
older mice. In fact, a recent study showed that hind limb of WT LRRK2, Lrrk, has been seen to increase the neu-
defects and loss of DA neurons in the SNpc can be seen in rotoxicity of pathological Tau when the human mutated
2-year-old PRKN knock-out (KO) mice [137]. Thus, mice R406W form of Tau is expressed [148]. The Drosophila
lacking PINK1 or PRKN might be used to better under- model can therefore be useful in understanding the inter-
stand the role and the involvement of these genes in vivo. action of LRRK2 and Tau pathology. Moreover, as C.
Nevertheless, the time required for these mice to develop elegans and Drosophila do not naturally express α-syn,
neurodegeneration could be a major limiting factor for the function of LRRK2 can additionally be studied in the
using this model in neuroprotective studies. Recently, a absence of endogenous α-syn.
non-human primate model with a genetic deletion of In mice, G2019S LRRK2 overexpression and Knock-
PINK1 was generated. This model presents behavioral In (KI) models generate synaptic alterations, impaired
abnormalities at 1.5 years of age and DA neuron degen- DA transmission, behavioral abnormalities and
eration in the SNpc at 3 years of age, without changes in increased Tau phosphorylation [150–156]. These
mitochondrial morphology [138]. It is still unknown if rodent models usually lack degeneration of DA neu-
these animals develop Lewy body-like inclusions. While rons in the SNpc, unless the mouse line overexpresses
the loss of PINK1 more closely reflects parkinsonian G2019S LRRK2 under the neuron-specific platelet-
phenotypes, this model is not yet fully characterized. derived growth factor beta (PDGF-β) promoter. These
Further studies are needed to assess its importance as a transgenic mice show striatal denervation, DA neuron
PD animal model (Table 1). Although promising and rel- degeneration, and increased phosphorylated Tau pro-
evant to PD, no PRKN-transgenic model in non-human tein in the SNpc at 16 months of age [157]. Features of
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 11 of 25

neuroinflammation, as well as autophagic and mito- DA axonal denervation in the striatum, DA neuron loss
chondrial abnormalities are also present despite the in the SNpc, and motor impairments after 2 weeks [165].
absence of synucleinopathies [158, 159]. More recently, The MPTP treatment accelerates the phenotype seen in
neurodegeneration has been reported in a mouse line KO models alone by increasing the oxidative stress bur-
expressing G2019S LRRK2 in DA neurons under the den [163] (Table 1).
TH promoter. The alteration drives a progressive loss
of DA neurons in the SNpc by 15 months of age, with UCH‑L1
additional neuronal loss observed in the olfactory bulb UCH-L1 is a deubiquitinating enzyme believed to be one
and locus coeruleus. By 24 months of age, this pheno- of the most abundant proteins in neurons, accounting for
type is accompanied by reduced synaptic vesicles in the about 1%–5% of the total amount of proteins in the brain
DA neurons, motor deficits, and an increased amount [172]. The first association between the UCH-L1 gene
of phosphorylated α-syn [160] (Table 1). Overall, and PD was revealed in 1998, following the identification
LRRK2 mutant mice might be used to study the patho- of the autosomal mutation I93M in the pedigree of a Ger-
genesis of PD and to identify neuroprotective therapies man family [173]. Although this mutation is rare, UCH-
aimed at inhibiting its kinase activity or its downstream L1 localizes with Lewy bodies in some sporadic cases of
targets. PD [174, 175]. While UCH-L1 is involved in the clear-
ance of proteins via the ubiquitin-proteasome system,
a recent study also suggests that UCH-L1 can modulate
DJ‑1 mitochondrial functions by regulating the expression of
First discovered as a novel oncogene in 1997 [161], Mitofusin-2 [176] (Fig. 2). To date, there are relatively few
the DJ-1 gene encodes a protein of the peptidase C56 transgenic animal models for UCH-L1. In mice, the dele-
family. It is also known for its function against oxida- tion of UCH-L1 induces axonal degeneration in sensory
tive stress [162, 163] via its direct interaction with and motor nerve terminals [177–179] without affect-
mitochondria [164] and DA neurons in the SNpc, ing DA nigral neurons [175]. The only transgenic mouse
which drive the nigrostriatal motor pathway inhibi- model that affects the DA neurons of the SNpc is the
tion (Fig. 2) [165]. Deficiency of DJ-1 has been identi- UCH-L1 I93M mice, which overexpress I93M mutated
fied as a causative factor in familial PD with recessive UCH–L1 under the control of the PDGF-β neuron-spe-
inheritance [166], where it downregulates the level cific promoter [180]. Although these mice may be useful
of lysosomal 70 kDa heat-shock cognate protein. By for studies aimed at discovering neuroprotective thera-
simultaneously inhibiting the activation of chaperone- pies for PD by targeting UCH-L1 activity, this approach
mediated autophagy, DJ-1 deficiency may augment is limited because UCH-L1 I93M transgenic mice lack
α-syn aggregation [167] and mitochondrial abnor- α-syn inclusions. Furthermore, the degeneration of
malities [168] in PD. Although DJ-1 KO mice exhibit DA neurons and motor deficits can take more than 20
alterations in DA metabolism, the KO alone is not suf- months to develop [180]. To accelerate the degeneration
ficient to induce loss of DA neurons and PD-like signs of SNpc DA neurons, this model has been previously
in young mice. However, in older mice, there are sig- combined with viral α-syn overexpression [175]. More
nificant DA neuronal losses and motor deficits [169]. recently, knock-down (KD) of the UCH-L1 ortholog gene
A similar age-dependent difference is also visible in (dUCH) in a Drosophila PD model was created using the
the Drosophila model with two existing orthologs for GAL4-UAS system. This model exhibits motor altera-
DJ-1 [170]. While the major limitation of this model tions, degeneration of DA neurons, and a reduction in
lies within the prolonged time required for a phenotype the level of DA in the brain [181], thus making this model
to appear, it remains promising, as ageing seems to be appropriate for fast screening approaches to identify
a crucial factor in progressive neurodegenerative dis- UCH-L1 interactors (Table 1).
eases like Parkinson’s. Because PD similarly evolves in
older adults, this progressively developing model may
be suitable for targeting the earlier phases of the phe- GBA1
notype induction and its subsequent manifestation. Mutations in GBA1 are among the most common genetic
Recent studies have used MPTP hybrid models that risk factors for PD and Lewy body dementia [182, 183].
take advantage of the usual role DJ-1 has as a negative The GBA1 gene is located on chromosome 1q21 and
regulator of the inflammatory response, alleviating neu- encodes the lysosomal glucocerebrosidase enzyme
roinflammation, and playing an essential role in neurode- (GCase) [184]. Thus, GBA1 mutations induce a defi-
generation [171]. DJ-1 KO mice tend to present PD-like ciency of GCase activity that leads to an accumulation
pathology after MPTP treatment, resulting in accelerated of glycosphingolipids [185]. Clinical, epidemiological,
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 12 of 25

and experimental studies have confirmed a connection features lead to DA neuron death and motor phenotypes,
between PD and Gaucher disease, a prevailing autoso- making them an appealing tool for studying PD (Table 1).
mal recessive lysosomal storage disorder [186]. Recently,
GBA1-derived PD clinical cases have shown impaired DA Transcription factors
neurotransmission early in the pathogenesis, although During the development of midbrain DA neurons, tran-
the underlying mechanisms are still not well understood. scription factors play key roles in specifying and dif-
So far, approximately 130 different GBA1 mutations have ferentiating neural progenitors. Interestingly, most of
been observed in patients with PD. The most frequent these transcription factors remain expressed in the adult
cases with declined GCase activity are the L444P and brain [199, 200]. Indeed, Lmx1a/b, Otx2, Foxa1/2, Pitx3,
N370S GBA1 mutations [185, 187, 188]. Recent stud- Nurr1, and En1/2 are present throughout development
ies have focused on the association between mutated and are required for the survival of midbrain DA neu-
GBA1 and PD, highlighting the possibility that lysosomal rons [201–204]. Genome-wide association studies have
impairment and altered GCase activity could facilitate revealed genes that may contribute to PD [205]. Among
the proliferation of α-syn aggregates [188–190]. Today, them, genetic variants of human transcription factors
several animal models of GBA1 have been created [182]. such as Lmx1a and Lmx1b were found [204, 206–208],
GBA1-associated PD mouse models combine a GBA1 with the expression of Lmx1b being notably decreased in
mutation with overexpression of α-syn mutations to gen- the DA neurons of PD patients [209]. Lmx1a and Lmx1b
erate α-syn aggregation and pronounced PD-like signs. are LIM homeodomain transcription factors essential for
Additionally, different KI models carry the human L444P the development of midbrain DA neurons [210–213] and
GBA1 gene [191]. GBA1 L444P homozygous mice show are still expressed in post-mitotic midbrain DA neurons
an increase of α-syn accumulation in the striatum and [214–216]. Conditional deletion of Lmx1a and Lmx1b
astrogliosis at 1 year of age [192]. GBA1 L444P heterozy- genes in mouse DA neurons induces progressive neuro-
gous mice develop mitochondrial dysfunction, increased degeneration in the SNpc and VTA [203, 217]. Lmx1a
ROS production, impaired neuronal autophagic degra- and Lmx1b are particularly important in regulating mito-
dation [193], and higher levels of α-syn [194], but fail to chondrial [217] and autophagic-lysosomal functions
develop α-syn aggregates even by 24 months of age [194]. [209]. Moreover, loss of Lmx1a and Lmx1b leads to α-syn
Unlike L444P, heterozygosity for N370S does not affect pathology with the accumulation of α-syn in both DA
phenotype progression in A30P-SNCA mice [193], and axons and cell bodies [217]. Specific deletion of Lmx1a
N370S homozygote mice die at birth. Injection of adeno- and Lmx1b in adult DA neurons also leads to progres-
associated virus (AAV) expressing N370S GBA1 in the sive loss of DA neurons, α-syn pathology, and motor
striatum of A53T-SNCA mice results in increased α-syn impairments [209, 217]. Depletion of Otx2, Foxa1/2, and
protein, defects in mitophagy, and abnormal autophagy Pitx3 leads to a reduction of midbrain DA neurons with
[191, 193]. GBA1-associated PD models can also be motor deficits [218–223]. While heterozygous KO mice
found in Drosophila and C. elegans. In these PD-GBA for Nurr1 and En1 develop progressive loss of DA neu-
Drosophila models, an increased aggregation of mutant rons with motor deficits [224, 225], total depletion of
α-syn A53T is observed, causing enhanced DA neuronal Nurr1 [224, 226] and En1 [227] in midbrain DA neurons
loss and exacerbating the motor and non-motor pheno- is embryonically lethal. Lastly, KO of the transcription
types [195]. Drosophila expressing the mutant human factor c-Rel can induce α-syn aggregation in the SNpc,
N370S and L444P variants exhibit a significant decrease midbrain DA neuronal loss, and motor deficits [228]
in GCase activity and present parkinsonian features with (Table 1). Overall, several signs of PD can be reproduced
DA cell death, defective locomotion, and a shorter lifes- by modulating the expression of DA transcription fac-
pan [196]. Overall, fly models expressing human WT tors; however, the phenotype is restricted to DA neurons.
or N370S and L444P GBA1 provide an interesting tool Most of these models also require multiple crosses to
to assess the contribution of defective GCase function obtain a conditional deletion in adult mice, which could
to PD development. In C. elegans expressing a human thus represent a limiting factor.
α-syn, KD of GCase ortholog, C33C12.8, increases aggre-
gation of α-syn [197], similar to what has been described Mitochondrial impairment
in other animal models [198]. In sum, GBA1-associated Several lines of evidence have previously linked mito-
models of PD provide insight into the pathogenesis by chondrial dysfunction to PD pathogenesis [229, 230].
replicating many hallmarks of the disease. GBA1 models This is supported by a large set of PD-associated genes
show increased α-syn accumulation, disruption of lyso- that are involved in mitochondrial function [231, 232].
somal homeostasis, exacerbated endoplasmic reticulum Furthermore, α-syn and neurotoxins linked to PD,
stress, and mitochondrial dysfunction. These cellular including MPTP and rotenone, are known to inhibit
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 13 of 25

MCI activity [233]. MCI deficiency was also reported eight different identified missense mutations of SNCA
in DA neurons of the SNpc for human PD post-mortem (A53T/E/V, A30P/G, E46K, H50Q and G51D) [244],
brains [234]. One of the first transgenic mouse models gene duplication, and triplication have been linked to the
of PD to induce mitochondrial impairment in DA neu- accumulation of pathologic α-syn in the brain [245]. This
rons was created by crossing DJ-1-deficient mice with a new knowledge gave rise to several animal models mim-
mouse strain encoding a mutated mitochondrial poly- icking α-syn pathology. Transgenic models expressing
merase gamma, resulting in an accelerated accumulation WT, A53T, A30P, and E46K SNCA mutations have been
of mitochondrial DNA errors. Even at 1 year of age, these utilized to recapitulate PD pathology in vivo. However,
mice do not exhibit behavioral abnormalities, degenera- to date, there are no reported studies on A53E, A53V,
tion of nigrostriatal DA neurons, or evidence of neuroin- A30G, H50Q, or G51D transgenic models, which could
flammation [235]. A similar phenotype has recently been be of interest for future investigations.
observed in mice lacking PRKN [236].
In mice, conditional deletion of the Ndufs4 gene (which WT and truncated human α‑syn
encodes a subunit of MCI) in DA neurons results in loss As one of the first transgenic animal models of α-syn,
of striatal DA at 9 months, followed by increased α-syn the mouse line 61 (M61) is generated by overexpressing
phosphorylation in DA neurons at 24 months of age. human WT α-syn using the neuron-specific Thymocyte
However, deletion of Ndufs4 in DA neurons does not differentiation antigen 1 (Thy1) promoter [246]. Mito-
cause motor deficits or DA neuron degeneration in the chondrial dysfunction and neuroinflammation have been
SNpc [237]. One possible explanation for this phenotype described in these mice [247, 248]. Moreover, motor defi-
is that Ndufs4 KO results in about 65% reduction of MCI cits and α-syn inclusions appear within a few months of
activity [237] and DA neurons could compensate for the age, although nigral DA neurons are only mildly affected.
lack of oxidative phosphorylation [238]. Recently, another In fact, while a decreased amount of striatal DA and axonal
model of MCI disruption by deletion of the essential MCI denervation are observed, no degeneration of DA neurons
subunit Ndufs2 in DA neurons was generated. Com- in the SNpc is reported [246, 249]. M61 mice have thus
pared to the Ndufs4 KO model, the KO of Ndufs2 almost been used to test candidate drugs targeting α-syn aggrega-
completely disrupts the oxidative phosphorylation activ- tion and axonal denervation. The MI2 mouse line express-
ity in DA neurons. Deletion of Ndufs2 induces loss of ing C-terminal-truncated human α-syn under the TH
DA axons in the dorsal striatum by 1 month of age, fol- promoter shows α-syn aggregates in DA neurons by 1.5
lowed by motor deficits after 1 to 2 months. These motor months of age. By 9 months, motor impairments appear;
deficits are accompanied by a decrease in the number of by 12 months, a significant loss of DA neurons in the SNpc
cells expressing TH in the SNpc. However, despite the can be seen [250]. Additionally, because MI2 mice pos-
decrease in TH expression, there is no loss of dopamin- sess a null endogenous α-syn background, human α-syn
ergic cell bodies [238]. No α-syn aggregates have been seeding is facilitated. However, since the α-syn expression
observed in this model, but it might be because that is restricted to DA neurons, the MI2 mouse line does not
these mice die at 5–6 months of age before developing recapitulate synucleinopathies in other brain regions.
α-synucleinopathies [238]. Additional characterization
of neuroinflammatory and autophagic features is still E46K human α‑syn
needed. However, the Ndufs2 KO mouse model remains Identified within a Spanish family with autosomal domi-
of interest in the study of neuroprotective therapies aim- nant parkinsonism and dementia, the cortical and sub-
ing to rescue oxidative phosphorylation or MCI activity. cortical Lewy body pathology found was attributed to
a shared nonconservative heterozygous E46K mutation
α‑syn models within α-syn [251]. While the mutant mouse PD models
The α-syn protein, encoded by SNCA, has a central role created based on this mutation are still recent and war-
in PD, although its physiological function is not yet rant further research, this initiative can provide insight
fully understood. Usually clustering into monomers and into familial PD and synucleinopathies. Transgenic
tetramers [239, 240], α-syn assembles into higher-order mouse lines carrying the PrP (Prion protein)-driven
structures under pathological conditions. These oligom- E46K mutation have been generated. The mouse line 47
ers, protofibrils, and fibrils form insoluble aggregates (M47) shows higher levels of α-syn transgene expres-
that are toxic to neurons [241]. As a principal constitu- sion, with motor impairments starting at 15–16 months
ent of Lewy bodies [242], these aggregates can not only of age. These mice develop α-syn inclusions in the spinal
alter the integrity of the cell membrane, but may also dis- cord, brainstem, deep cerebellar nuclei, motor cortex,
rupt the functions of mitochondria, the Golgi apparatus, and most of the thalamus. The inclusions and affected
and the endoplasmic reticulum [243] (Fig. 2). At least areas are accompanied by phosphorylation of α-syn,
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 14 of 25

significant astrocytic gliosis, elevated reactive micro- phenotype with evidence of dystrophic neurites. They
glia, and Tau inclusions [252]. DA neurons of the SNpc present increased phosphorylated α-syn and aggregation,
remain spared of α-syn inclusions. These results may similar to patients [264–267]. These inclusions become
corroborate those observed in rat models with the same apparent between 8 to 16 months of age in homozygous
mutation, where no loss of DA neurons or striatal termi- M83 mice, resulting in motor impairments. Like M47
nals was reported [253]. mice, the highest density of these inclusions is localized
in the spinal cord, brain stem, deep cerebellar nuclei,
A30P α‑syn white matter, and some thalamic regions. An identical
The A30P α-syn mutation was first detected in a German inclusion profile arises in hemizygous M83 mice between
family [254]. The few existing transgenic mouse strains 22 and 28 months of age when animals spontaneously
that model the A30P mutation include overexpression develop motor dysfunction [264]. No loss of DA neurons
of the human A30P α-syn gene under the Prp promoter has been reported, and there is no alteration of striatal
(Prnp-A30P) [255] or the Thy1 promoter (Thy1-A30P) DA at 12 months of age in M83 homozygous mice [268].
[256], and a KI mouse model with an introduced A30P Altogether, this mutation owes its pathological nature to
point mutation in the WT gene [255]. All these A30P its tendency to form α-syn inclusions, much like in the
models show an increase and accumulation of α-syn in clinical setting. While the location of pathological lesions
neuronal cell bodies with age. However, it is most robust in mice does not precisely mirror the human condition,
in the Prnp-A30P mice. For Thy1-A30P α-syn transgenic they do share many similarities, such as neuroinflam-
mice, abnormal α-syn protein is observed in several brain mation, as well as autophagic and mitochondrial dys-
regions like the superior colliculus or the cerebellum, but function [269–272]. This human A53T mutation model
α-syn pathology is spared in the striatum and SNpc [255]. is proposed to be a valuable asset in screening potential
Mitochondrial oxidative stress and autophagy defects therapeutics that inhibit or reverse α-syn aggregate for-
are also reported in A30P models [257]. Only the neu- mation or spreading.
ronal cell loss in the SNpc does not seem to be consist-
ently detectable. While Thy1-A30P mice show reduced α‑syn preformed fibrils (PFFs)
TH levels in the SNpc at 8 and 11 months [256], the PFFs are first generated from monomeric recombinant
loss of DA is not visible in the strains [255, 258]. Loco- α-syn. When fragmented by sonication, PFFs can phos-
motor disabilities and α-syn aggregation seen in rodent phorylate endogenous α-syn into its pathological state
models are similarly observed in flies overexpressing the [273]. In mice, α-syn spreading is enhanced with PFFs
A30P mutant form of α-syn. Flies also exhibit selective generated from brain homogenates of aged sympto-
loss of DA neurons when A30P is expressed in all neu- matic α-syn mice or human samples, or recombinant
rons [259, 260]. In C. elegans, A30P α-syn models are synthetic α-syn fibrils (Fig. 2). In WT mice, injection of
mild. Compared to control animals, worms expressing mouse PFFs in the dorsal striatum induces hyperphos-
A30P α-syn in muscles have modest reduction of move- phorylation of α-syn within 30 days [274]. Degeneration
ment speed and increased rate of paralysis [261]. In a C. of DA striatal fibers and cell bodies in the SNpc, as well
elegans model of A30P under the control of the DAT-1 as motor impairments, occurs 6 months post-injection
(C. elegans DAT) promoter, the expression is restricted [274]. Whole-brain homogenate extracts of parkinsonian
to DA neurons. The worms exhibit DA neuron-specific symptomatic M83 mice can be injected into the M83
dysfunction caused by accumulation of α-syn but do mice at birth to accelerate the development of the phe-
not show significant neurodegeneration compared to notype and α-syn aggregation [275–277]. There is also a
controls, even at 15 days of age [262]. Overall, the A30P robust inflammatory response before end-stage paraly-
models show mild phenotypes. The progressive and rela- sis occurs by 8 to 16 months in homozygous mice and by
tively long development of pathological abnormalities, 22 to 28 months in heterozygous mice [278]. Similarly,
such as α-syn accumulation and motor disorders, may extracts from post-mortem PD brain tissues have previ-
provide an interesting approach to study the early stages ously been used in the intranigral and intrastriatal inocu-
of PD. lation of WT mice and macaque monkeys. The fractions
enriched with nigral Lewy bodies have demonstrated
A53T human α‑syn the ability to induce pathogenic effects, such as progres-
The A53T mutation in the α-syn gene was initially iden- sive nigrostriatal neurodegeneration and the accumu-
tified in Italian and Greek pedigrees [263]. The PrP- lation of pathological α-syn, which cannot be achieved
driven mouse line 83 (M83) was the first to be genetically by non-Lewy body fractions or vehicle buffers [279]. A
engineered to overexpress human A53T α-syn. M83 new alternative created with the bacterial artificial chro-
mice show a mid-to-late onset of neurodegenerative mosome plasmid consists of A53T overexpressing mice
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 15 of 25

injected with recombinant synthetic α-syn. This hybrid interest [301]. This technique thus makes it feasible to
model produces phosphorylated α-syn inclusions and study the possible transmission of α-syn pathology from
striatal DA denervation within 2 weeks post-injection the periphery to the central nervous system [302]. In gen-
[280]. Within 1 month, there is 25% DA neuronal loss eral, α-syn overexpression in the SNpc results in the pro-
in the SNpc. Motor impairments were reported at 2 gressive DA neuron loss, and DA projection decrease in
months post-injection [280], but they can be expected the striatum within weeks to months, and models early
to appear earlier since DA denervation appears before and late hallmarks of PD pathogenesis, depending on the
this time point [277]. In cell-based models, PFFs were model organism [300, 303–305]. However, studies have
shown to additionally produce autophagic and mito- yielded variable results, showing a range from slight to
chondrial dysfunction [281, 282]. Lastly, recent studies substantial loss of DA neurons. Several factors, includ-
in 26-month-old non-human primates have shown that ing virus titer or serotype, age, sex, strain, or species of
PFFs are also sufficient to drive phosphorylated α-syn the animal, can strongly influence the outcomes obtained
accumulation and DA neuronal loss by 3 months post- (see [306, 307] for reviews). In rodents, viral α-syn over-
injection [273]. However, the injection site of the PFFs is expression results in an approximate 40% DA cell loss
consequential in further characterizing the α-syn seeding in the SNpc, accompanied by motor deficits at 8 weeks
and spreading [274, 277, 283]. We cannot overlook that post-injection [308]. Less commonly used, non-human
α-syn transmission also occurs in the periphery and that primates receiving intranigral AAV injections of WT or
α-synucleinopathy in the brain may develop via the gut- A53T α-syn show a ~ 30% loss of nigral DA neurons 8
to-brain axis [284]. Inoculation of the rodent gut with weeks post-injection. Like rodents, non-human primates
PFFs results in midbrain DA neuron loss, α-syn histopa- also develop motor deficits with a progressive deteriora-
thology, and motor defects in a temporal manner [285– tion of motor coordination after 16 weeks, albeit with a
287]. Nevertheless, despite differences from the human greater variability [309]. Non-human primates enable a
pathology, PFFs can reproduce specific aspects or stages more extended period of studies on the effects of α-syn
of α-syn pathology, as well as neurodegenerative and injections than their rodent counterparts [310, 311].
neuroinflammatory hallmarks of PD [288]. Overall, both Moreover, monkeys were found to be more vulnerable to
in vitro and in vivo, fibril formation and aggregation are neurodegeneration and pathologies induced by injections
not synonymous with pathological aggregation and LB with viral vectors that encode A53T α-syn [311]. Overex-
formation. Therefore, strict quality control must be taken pression of α-syn in the midbrain typically leads to mito-
so that the pathogenicity of the PFFs used ensures repro- chondrial dysfunction [312], impaired autophagy [313],
ducible results [284, 289, 290]. Lewy body-like structures [300, 314], and an early and
persistent inflammatory response [315–318]. Recently,
Non‑mammalian models of α‑syn a light-inducible α-syn aggregation system (LIPA) was
Non-mammalian models, including those based on designed to regulate spatiotemporal protein aggregation
C. elegans and D. melanogaster, do not produce α-syn [319]. This system could control α-syn aggregation into
endogenously. In C. elegans [291–293] and Drosophila insoluble deposits that mimic key features of Lewy bod-
[294–296], the overexpression of human WT and A53T ies. LIPA is encoded in a viral vector and injected into
α-syn in an ubiquitous or DA-specific manner induces the SNpc. The α-syn aggregation is then induced by light
α-syn aggregates, mitochondrial fragmentation, motor stimulation through an optical fiber implanted above the
impairments, and loss of DA neurons. These non-mam- injection site. Following repeated optogenetic stimula-
malian models offer an interesting way for rapid screen- tions, the nigrostriatal transmission is compromised,
ing of anti-aggregation targets. However, they might be leading to Lewy body-like structure formation, neuro-
too simplistic to transpose the results directly to complex degeneration, and motor impairments within 2 months.
and still not fully understood mechanisms of aggrega- This inducible model of α-syn aggregation allows for real-
tion, propagation, and toxicity of synucleinopathies in the time monitoring of α-syn aggregation and Lewy body-like
human brain. formation with high spatiotemporal control. Altogether,
viral vectors are very versatile and powerful tools that
Viral vector‑mediated models offer the opportunity to closely mimic PD pathology by
α‑syn viral expression inducing the overexpression of α-syn within multiple
Another alternative to model PD in animals is to overex- animal species (Table 1). Viral overexpression allows us
press WT or mutated α-syn, including A53T and A30P to study α-synucleinopathy more precisely and to fol-
forms [297], using lentiviral [298] or AAV vectors [299, low the progressive development of PD-like phenotypes.
300]. These viral vectors can transduce diverse cell types Lastly, this tool may also target other non-dopaminergic
and drive the expression of α-syn in the brain region of
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 16 of 25

systems, following the impact of α-syn in the periphery against PD. However, PD is a highly heterogeneous dis-
or other neuronal cell populations. ease involving several factors and pathways that may dif-
fer among clinical cases. Therefore, none of the existing
Viral neuromelanin (NM)‑like production and future models will replicate the entire spectrum of
Neurodegeneration is particularly prominent within brain clinical features listed in PD. In this review, we tried to
regions containing NM. In 1919, a visually noticeable loss summarize the most relevant PD animal models, their
of pigmented neurons in the SNpc was first reported by respective advantages and disadvantages, as well as their
Konstantin Tretiakoff [320]. This pigmentation loss in the ability to reproduce the main hallmarks of PD.
brains of PD patients referred to a decrease in NM con- The choice of the animal model must be based on the
centration, which was less than 50% of the expected levels PD features addressed by the question the experimenter
for age-matched healthy individuals [321]. NM pigment seeks to answer. Neurotoxin-induced animal models
appears black and consists of melanin, proteins, lipids, remain popular due to their cost-effectiveness in generat-
and metal ions. It can be found in different human cen- ing a PD-like phenotype in a relatively short time span.
tral nervous system neurons and is particularly abundant Thus, they are commonly used in drug validation for
in DA neurons of the SNpc and noradrenergic neurons of symptomatic treatment of PD or cell replacement ther-
the locus coeruleus. The pigment itself is contained within apy. On the other hand, to investigate the function of PD-
specific types of lysosomes fused with autophagic vacu- linked genes in disease development, transgenic models
oles [322]. Additionally, DA and norepinephrine appear to should be considered. Other questions concerning the
be the principal substrates in its synthesis. However, NM targeting of α-syn pathology can also be answered in ani-
may have both a protective and a toxic effect, depending mal models injected with PFFs or viral vectors encoding
on the conditions of the neuronal environment. Under SNCA gene copies. In the absence of a suitable model
physiological conditions, NM is proposed to have a pro- fully recapitulating the targeted PD features of interest,
tective role via iron binding. In PD, iron-bound NM can a possible solution could be to complement the pheno-
easily release excess iron, producing a toxic effect via types by combining some of the listed models.
redox processes. Moreover, the iron overload of NM can The selection of animal species is equally as important.
catalyze DA oxidation, forming DA-o-quinone, and modi- Although the translational results to humans are valuable
fying proteins that trigger neurotoxic effects [323] (Fig. 2). in mammalian models, the use of rodents and primates
Yet, the structure and function of human NM in PD for drug or gene screening is untenable. C. elegans and
have proven to be difficult to investigate due to the lim- Drosophila could be considered to identify novel neuro-
ited quantities available for extraction from human brain protective targets [293, 329]. However, the simplicity and
tissues. Furthermore, animal models including rodents lack of similarity with humans are limitations. Moreo-
lack NM. Nevertheless, recent in vivo models have been ver, research in PD should not be limited to the use of in
explored, reporting microglial activation via intranigral vivo models. Although animals offer a better pre-clinical
synthetic NM injections [324–326]. A new approach was prediction of a drug effect, in vitro models could provide
applied in rodents to virally express human tyrosinase complementary information on the underlying molecular
(hTyr) in the SNpc. This model shows NM-like pigment mechanisms [330]. Still, most in vitro-based models can-
accumulation in SNpc DA neurons in an age-dependent not reproduce the non-cell autonomous impact of the
manner. In fact, overexpression of hTyr recapitulates the complex cell network in the brain. The near future could
principal hallmarks of PD: mice show mitochondrial and shed light on the use of human brain organoids to per-
autophagic dysfunction, as well as neuroinflammation. form drug or gene screenings, although additional char-
They also have impaired DA release, striatal denerva- acterization of these emerging models will be required
tion, loss of DA neurons in the SNpc, and motor deficits [330, 331].
by 4 months post-injection [327]. This is accompanied by
Lewy body-like structures and autophagic dysfunction Conclusion
within NM-like positive neurons [327, 328]. Therefore, Despite efforts devoted to interpreting the pathogenesis
this model provides a valuable experimental tool to study of PD, the initial source of neuronal degeneration remains
the effects of NM production and accumulation on neu- unclear. There is considerable evidence to suggest that
ronal function and viability (Table 1). α-syn aggregation, neuroinflammation, as well as lysoso-
mal and mitochondrial dysfunction could all play a key
Discussion role in neurodegeneration [3]. Basic research has yet to
Modelling PD pathogenesis remains a difficult task. reconcile these features, discriminating causes from con-
Several animal models have been developed to under- sequences in the PD pathogenesis. Existing animal mod-
stand the pathogenesis and test new drug candidates els, many of which recapitulate multiple disease features
Dovonou et al. Translational Neurodegeneration (2023) 12:36 Page 17 of 25

from cellular pathology and pathogenesis to motor and Availability data and materials
Not applicable.
non-motor symptoms, open new possibilities. However,
the wide range available can make choosing a model for
a given study challenging. This task becomes particularly Declarations
complex if the study addresses multiple aspects of PD. Ethical approval and consent to participate
This review compiles information on the diversity of ani- Not applicable.
mal models, and is therefore, a support for researchers to Consent for publication
select the optimal animal model for their study. Carefully Not applicable.
constructed research models are an essential first step to
Competing interests
understand the disease and discover novel therapies, pos- The authors declare that they have no competing interests.
sibly improving the quality of life and the clinical fate of
patients.
Received: 13 March 2023 Accepted: 19 June 2023
Abbreviations
6-OHDA 6-Hydroxydopamine
AAV Adeno-associated virus
α-syn α-synuclein
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